Arterial thrombosis causes heart attacks and strokes and is the leading cause of morbidity and mortality in the United States. Recurrent thrombosis is common despite current therapies.
Protein disulfide isomerase (PDI) is a member of an extended family of oxidoreductases, best known as endoplasmic reticulum-resident enzymes. These enzymes catalyze posttranslational disulfide bond formation and exchange and serve as chaperones during protein folding (Hatahet et al. Antioxid Redox Signal. 2009, 11(11), 2807-2850). PDI has been identified at many diverse subcellular locations outside the endoplasmic reticulum. It has biological functions on the cell surfaces of lymphocytes, hepatocytes, platelets, and endothelial cells (Manickam et al., Br J Haematol, 2008, 140(2), 223-229; Hotchkiss et al., Biochim Biophys Acta. 1998, 1388(2), 478-488; Essex et al., Br J. Haematol. 1999, 104(3), 448-454; Burgess et al., J. Biol Chem. 2000, 275(13), 9758-9766; Bennett et al., J. Immunol. 2000, 164(8), 4120-4129). PDI is rapidly secreted from both endothelial cells and platelets during thrombus formation in vivo (Cho et al., J. Clin Invest. 2008, 118(3), 1123-1131; Jasuja et al., Blood 2010, 116(22), 4665-4674). Inhibition of PDI using neutralizing antibodies blocks thrombus formation in several thrombosis models (Bennett et al., J. Immunol. 2000, 164(8), 4120-4129; Cho et al., J. Clin Invest. 2008, 118(3), 1123-1131; Jasuja et al., Blood 2010, 116(22), 4665-4674; Reinhardt et al.; J. Clin Invest. 2008, 118(3), 1110-1122). Inhibition of PDI in these models abrogates not only platelet accumulation at the injury site but also fibrin generation. These observations demonstrate a critical role for extracellular PDI in the initiation of thrombus formation. While currently available antithrombotic agents inhibit either platelet aggregation or fibrin generation, inhibition of secreted PDI blocks the earliest stages of thrombus formation, suppressing both pathways and indicating that PDI could be a useful target in the pharmacological control of thrombus formation. However, potential complications of inhibiting PDI are the ubiquitous distribution and critical function of intracellular PDI. Presently, available inhibitors of PDI are sulfhydryl-reactive compounds that bind covalently and are non-selective, acting broadly on thiol isomerases (Karala et al., FEBS J. 2010, 277(11), 2454-2462) or are cytotoxic (Lovat et al. Cancer Res. 2008, 68(13), 5363-5369; Khan et al. ACS Chem. Biol. 2011, 6(3), 245-251). Thus, there is a clear need for new approaches and new targets in the prevention and treatment of arterial thrombosis, such as new agents that interfere with PDI activity but are otherwise selective and well tolerated in therapeutic contexts.